Chronic obstructive pulmonary disease (COPD) is believed to be causally related to genetic, environmental and host factors, whose number and interaction are unknown. Severe alpha1-antitrypsin (AAT) deficiency, ZZ(Pi) phenotype, is an established genetic factor and cigarette smoking an important environmental factor. Differences among ZZ homozygotes and smokers in susceptibility to the disease suggest some other inherited, environmental or host factors play a role. Our ongoing studies indicated COPD patients of the MM, MZ and ZZ phenotype differ from healthy control subjects of these same phenotypes in having higher mean neutrophil leukocyte (PMN) lysosomal elastase-like esterase activity (EEA), higher (though within normal range) PMN cell count, and a lifetime history of smoking a greater number of cigarettes. Among the COPD patients, EEA was elevated to a similar degree in those with bronchitis and/or emphysema. Our findings suggest the evaluated PMN lysosomal EEA is an associated variable of COPD and not necessary a result of the disease. Analysis of variance indicated that pack-years smoked was a signficant risk factor for COPD, accounting for 20% of the variability of pulmonary function derangement in MM COPD and for 6% in MZ and ZZ COPD group. EEA acted synergistically with pack-years smoked and also with TIA. Together these factors accounted for 41% of the variability of the pulmonary function derangement in the MM COPD and for 68% in the MZ and ZZ COPD group, with significant probability. Our major objectives are to enlarge our studies on the interaction of risk factors; to investigate additional protease-antiprotease relationships and mathematical models of interactions among risk factors. We will also investigate whether serum inhibitory activity for human PMN elastolytic activity is more discriminative of protease-antiprotease imbalance than the commonly measured serum trypsin inhibitory activity.